Modeling Meets Metabolomics-The WormJam Consensus Model as Basis for Metabolic Studies in the Model Organism Caenorhabditis elegans

Abstract

Metabolism is one of the attributes of life and supplies energy and building blocks to organisms. Therefore, understanding metabolism is crucial for the understanding of complex biological phenomena. Despite having been in the focus of research for centuries, our picture of metabolism is still incomplete. Metabolomics, the systematic analysis of all small molecules in a biological system, aims to close this gap. In order to facilitate such investigations a blueprint of the metabolic network is required. Recently, several metabolic network reconstructions for the model organism Caenorhabditis elegans have been published, each having unique features. We have established the WormJam Community to merge and reconcile these (and other unpublished models) into a single consensus metabolic reconstruction. In a series of workshops and annotation seminars this model was refined with manual correction of incorrect assignments, metabolite structure and identifier curation as well as addition of new pathways. The WormJam consensus metabolic reconstruction represents a rich data source not only for in silico network-based approaches like flux balance analysis, but also for metabolomics, as it includes a database of metabolites present in C. elegans, which can be used for annotation. Here we present the process of model merging, correction and curation and give a detailed overview of the model. In the future it is intended to expand the model toward different tissues and put special emphasizes on lipid metabolism and secondary metabolism including ascaroside metabolism in accordance to their central role in C. elegans physiology.

Keywords: Caenorhabditis elegans; metabolic pathways; metabolic reconstruction; metabolism; metabolomics.

Figure 1

Overview of published C. elegans metabolic reconstructions and their relation to consensus models described in this manuscript.

Figure 2

Initial reconciliation and merging of two previously published C. elegans reconstructions. (A) Genes from the two earlier reconstructions were compared using Wormbase, and metabolites were compared using BiGG. Sizable differences were seen in the scope of the content of the two reconstructions, and so they were curated and merged. (B) Duplicate reactions were identified and eliminated using the reaction formulae and information on charge and mass balances using the BiGG and MetaNetX databases. The calculations were performed using the COBRA Toolbox in MATLAB. (C) Several databases were used to reconcile various properties of the previous reconstructions. The filled boxes indicate the usage of the database, while color indicates the property reconciled.

Figure 3

Initial reconciliation and merging of two previously published C. elegans reconstructions. (A) Metrics obtained from the original Pathway Tools reconstructions of CeCon (Ma et al., 2017) and ElegCyc (Gebauer et al., 2016) and final metrics of the merged model, called WormCon. Data sources for the construction of CeCon and ElegCyc can be found in the original publications. (B) The iterative merging process used to generate the draft WormCon consensus model.

Figure 4

(A) Overlap of unique metabolite entities (first part of InChIKey) between the WormJam model and metabolites curated from literature (B) Histogram of Tanimoto similarities between all possible metabolite pairs in the WormJam model (red) and metabolites connected by a biochemical reaction (blue) (C) Heatmap of Tanimoto similarities between metabolites detected but not in the model (rows) and metabolites from the WormJam model (columns). Color scale is blue for 0 to red for 1. Whereas, 1 refers to a high structural similarity. The large red cluster contains mostly fatty acids and ascarosides. (D) Tanimoto similarity between guanosine and 1-Methylguanosine and 1,7-Dimethylguanosine (both detected but not in the model). These metabolites have high structural similarity indicating a potential relation as substrates and products in biochemical reactions. Both the methylated and dimethylated from are derived from RNA bound modified nucleotides, which are released upon degradation. (E) Structural similarity between bile acids from the model (cholic acid, glycocholic, and taurocholic acid) and glycodeoxycholic and taurodeoxycholic acid detected in different studies.